The NEP inhibitor prodrug sacubitril (N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester; IUPAC name 4-{[(1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoic acid, also known as AHU377) is represented by the following formula (A)

Sacubitril together with valsartan, a known angiotensin receptor blocker (ARB), forms a sodium salt hydrate complex, known as LCZ696, comprising the anionic forms of sacubitril and valsartan, sodium cations and water molecules in the molar ratio of 1:1:3:2.5, respectively (ratio of 6:6:18:15 in the asymmetric unit cell of the solid state crystal) (WO 2007/056546), and which is schematically present in formula (B).

Said complex is also referred to by the following chemical names: trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate or octadecasodium hexakis(4-{[(1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate) hexakis(N-pentanoyl-N-{[2′-(1H-tetrazol-1-id-5-yl)[1,1′-biphenyl]-4-yl]methyl}-L-valinate)-water (1/15) (IUPAC nomenclature).
LCZ696 acts as angiotensin receptor neprilysin inhibitor (ARNI) and is therefore useful particularly in the treatment of hypertension or chronic heart failure. Its utility has been confirmed by clinical trials, e.g. in the landmark PARADIGM-HF trial. Meanwhile, on Jul. 7, 2015, the FDA has approved LCZ696 for marketing.
Chemical synthesis routes to prepare NEP inhibitors and their prodrugs, in particular sacubitril, and its precursors have been described previously, e.g. in Ksander et al. J. Med. Chem. 1995, 38, 1689-1700; in U.S. Pat. No. 5,217,996 and in the international patent applications WO 2007/083774, WO 2007/083776, WO 2008/031567, WO 2008/083967, WO 2008/120567 WO 2009/090251, WO 2010/081410, WO 2011/035569, WO 2011/088797, WO 2012/025501, WO 2012/025502, WO 2013/026773, WO 2014/032627, WO 2015/024991, and WO 2015/037460 as well as in CN patent applications CN101362708, CN102260177, CN103483201, CN104557600, CN104725256, CN104725279, CN105017082, CN105061263, CN105085322, CN105152980, CN105168205, CN105198775, CN105237560, CN105330569, CN105481622, CN105566194, CN105601524 and CN105884656.
In particular CN101362708, WO 2013/026773, WO 2014/032627, WO 2015/024991 and CN105884656 deal with novel synthesis methods to provide the precursor compound
in particular
wherein R1 and R2 are independently of each other hydrogen or a nitrogen protecting group.
The process disclosed in WO 2013/026773 is depicted in the following scheme

The process disclosed in CN101362708 is depicted in the following scheme

The process disclosed in WO 2014/032627 is depicted in the following scheme

In addition, WO 2015/037460 discloses a process for obtaining an earlier intermediate, namely
in particular
by a process as follows:

The process disclosed in CN105884656 is depicted in the following scheme

However, these processes still have disadvantages such as potentially dangerous reactants or use of expensive catalysts and/or limited stereo-selectivity. Therefore, there is still a need to design chemical processes to provide cheap ways to access said starting materials for the synthesis of sacubitril which are suitable for industrial scale production under economically and environmentally favorable conditions and provide such drug substance precursors in high chemical purity and with high stereo-chemical selectivity.